Odin J. Naderer

Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir.

BACKGROUND Hypersensitivity reactions consist of a variable group of clinical findings and have been described for a wide variety of chemical compounds. OBJECTIVE This review characterizes the clinical profile of hypersensitivity to the nucleoside reverse transcriptase inhibitor abacavir sulfate. METHODS We performed a retrospective medical review of pooled adverse events data from approximately 200,000 patients who received abacavir in clinical trials, through expanded-access programs, or by prescription from 1996 through 2000. Screened cases of hypersensitivity were classified as either definitive or probable. Definitive cases were identified when initial symptoms resolved on interruption of abacavir therapy and returned on reintroduction of abacavir therapy. RESULTS A total of 1803 cases were identified, 1302 in the 30,595 patients participating in clinical trials or the expanded-access program and 501 in patients from the post-marketing experience. On review, 176 (9.8%) of these cases were considered definitive and the remainder probable. Based on the 1302 cases identified in clinical trials or the expanded-access program, the calculated incidence of hypersensitivity was 4.3%. Symptoms reported in > or = 20% of cases of this multiorgan reaction included fever, rash, malaise/fatigue, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea, among others. Respiratory symptoms occurred in 30% of cases and included dyspnea (12%), cough (10%), and pharyngitis (6%). In 90% of cases, hypersensitivity reactions occurred within the first 6 weeks after initiation of abacavir (median time, 11 days); after an initial reaction, rechallenge with abacavir resulted in the reappearance of symptoms within hours of reexposure. Hypotension was present in 25% of these rechallenge reactions. Among patients who received abacavir in clinical trials, the mortality rate was 0.03% (3 per 10,000 patients). CONCLUSIONS Hypersensitivity to abacavir is an idiosyncratic reaction and a distinct clinical syndrome characterized predominantly by systemic involvement. It can be expected to appear as a treatment-limiting event in approximately 5% of patients. The appearance of clinical symptoms consistent with this syndrome mandates immediate discontinuation of abacavir. Hypersensitivity to abacavir is an absolute contraindication to subsequent treatment with any formulation that includes this agent.

Retrospective Evaluation of Therapies for Staphylococcus aureus Endocarditis

We retrospectively evaluated antiinfective therapy for methicillin‐sensitive (MSSA) and methicillin‐resistant Staphylococcus aureus (MRSA) endocarditis in 54 patients who had 57 treatment courses for the disease. Three treatments were assessed: 27 nafcillin‐treated courses of MSSA endocarditis, 18 vancomycin‐treated courses of MSSA endocarditis, and 11 vancomycin‐treated courses of MRSA endocarditis. At baseline, patients with MSSA treated with vancomycin had more chronic conditions (p<0.01), a lower frequency of intravenous drug use (p<0.01), a lower hematocrit concentration (p<0.05), and a higher serum creatinine concentration (p<0.05) than the nafcillin group. Vancomycin‐treated patients had a higher complication rate during therapy (p<0.05) and a longer duration in an intensive care unit (p<0.01) than the nafcillin group. The trend was for a higher complete response rate in the nafcillin group (74% vs 50%, p=0.12), but no difference in mortality (22% vs 28%, p=0.73). Patients with MRSA infection treated with vancomycin had higher mortality than those with MSSA who received that drug (55% vs 28%, p=0.24). Patients with vancomycin‐treated MSSA endocarditis may have a poorer outcome than those who receive nafcillin, but this may be influenced by different or more severe clinical features. (Pharmacotherapy 1997;17(5):990–997)

National survey of once-daily dosing of aminoglycoside antibiotics

To evaluate the scope of once‐daily dosing of intravenous aminoglycoside antibiotics, a questionnaire was designed and mailed to a random sample of pharmacy directors at 500 acute care hospitals in the United States. The response rate was 68.4%. Nineteen percent of the respondents reported use of once‐daily dosing of aminoglycosides. Affiliation with a pharmacy residency program and the presence of a pharmacokinetic consultation service by the pharmacy department were associated with this practice (p<0.05). No other statistically significant differences were found. Reported indications, contraindications, and dosing were consistent with those found in the literature. The profession of pharmacy, as demonstrated by pharmacy residency programs and pharmacokinetic consultation services, appears to have been instrumental in implementing this method of dosing aminoglycosides.

Single-Dose Safety, Tolerability, and Pharmacokinetics of the Antibiotic GSK1322322, a Novel Peptide Deformylase Inhibitor

ABSTRACT GSK1322322 is a potent inhibitor of peptide deformylase, an essential bacterial enzyme required for protein maturation. GSK1322322 is active against community-acquired skin and respiratory tract pathogens, including methicillin-resistant Staphylococcus aureus, multidrug-resistant Streptococcus pneumoniae, and atypical pathogens. This phase I, randomized, double-blind, placebo-controlled, 2-part, single-dose, dose escalation study (first time in humans) evaluated the safety, tolerability, and pharmacokinetics of GSK1322322 (powder-in-bottle formulation) in healthy volunteers. In part A, dose escalation included GSK1322322 doses of 100, 200, 400, 800, and 1,500 mg under fasting conditions and 800 mg administered with a high-fat meal. In part B, higher doses of GSK1322322 (2,000, 3,000, and 4,000 mg) were evaluated under fasting conditions. Of the 39 volunteers enrolled in the study, 29 and 10 volunteers were treated with GSK1322322 and placebo, respectively. Upon single-dose administration, GSK1322322 was absorbed rapidly, with median times to maximum plasma concentration (Tmax) ranging from 0.5 to 1.0 h. The maximum observed plasma concentration (Cmax) and exposure (area under the concentration-time curve [AUC]) of GSK1322322 were greater than dose proportional between 100 and 1,500 mg and less than dose proportional between 1,500 and 4,000 mg. Administration of the drug with a high-fat meal reduced the rate of absorption (reduced Cmax and delayed Tmax) without affecting the extent of absorption (no effect on AUC). GSK1322322 was generally well tolerated, with all adverse events being mild to moderate in intensity during both parts of the study. The most frequently reported adverse event was headache. Data from this study support further evaluation of GSK1322322.

Safety, Tolerability, and Efficacy of GSK1322322 in the Treatment of Acute Bacterial Skin and Skin Structure Infections

ABSTRACT GSK1322322 represents a new class of antibiotics that targets an essential bacterial enzyme required for protein maturation, peptide deformylase. This multicenter, randomized, phase IIa study compared the safety, tolerability, and efficacy of GSK1322322 at 1,500 mg twice daily (b.i.d.) with that of linezolid at 600 mg b.i.d. in patients suspected of having Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). The primary endpoint was assessment of the safety of GSK1322322, and a key secondary endpoint was the number of subjects with a ≥20% decrease in lesion area from the baseline at 48 and 72 h after treatment initiation. GSK1322322 administration was associated with mild-to-moderate drug-related adverse events, most commonly, nausea, vomiting, diarrhea, and headache. Adverse events (86% versus 74%) and withdrawals (28% versus 11%) were more frequent in the GSK1322322-treated group. Treatment with GSK1322322 and linezolid was associated with ≥20% decreases from the baseline in the lesion area in 73% (36/49) and 92% (24/26) of the patients, respectively, at the 48-h assessment and in 96% (44/46) and 100% (25/25) of the patients, respectively, at the 72-h assessment. Reductions in exudate/pus, pain, and skin infection scores were comparable between the GSK1322322 and linezolid treatments. The clinical success rates within the intent-to-treat population and the per-protocol population that completed this study were 67 and 91%, respectively, in the GSK1322322-treated group and 89 and 100%, respectively, in the linezolid-treated group. These results will be used to guide dose selection in future studies with GSK1322322 to optimize its tolerability and efficacy in patients with ABSSSIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01209078 and at http://www.gsk-clinicalstudyregister.com [PDF113414].)

Safety, tolerability and pharmacokinetics of repeat dosing of the antibiotic GSK1322322, a peptide deformylase inhibitor: a randomized placebo-controlled study

OBJECTIVES GSK1322322 is a potent inhibitor of peptide deformylase, an essential bacterial enzyme required for protein maturation. In this two-part, double-blind, randomized, placebo-controlled, Phase 1 study (study identifier: PDF112668), the safety, tolerability and pharmacokinetics of single and repeat oral-dose GSK1322322 (500-1500 mg) in healthy adult and elderly volunteers were evaluated. PATIENTS AND METHODS Part A included GSK1322322 doses of 500, 750, 1000 and 1500 mg in healthy adults; Part B evaluated 1000 mg of GSK1322322 in healthy elderly volunteers. Volunteers received a single morning dose of a powder-in-bottle formulation of GSK1322322 or placebo on day 1, no dosing on day 2 and twice-daily dosing on days 3-12. RESULTS Of 52 enrolled volunteers, 40 and 12 volunteers were treated with GSK1322322 and placebo, respectively. Mean plasma GSK1322322 trough concentration increased with increasing dose and reached steady-state after 2 days of repeat dosing. After single dosing of GSK1322322, maximum plasma concentration and exposure (AUC) were dose proportional from 500 to 1500 mg. However, after repeat dosing, AUC values at steady-state increased slightly more than proportionally, possibly because of a slightly longer terminal elimination t½ after repeat dosing (compared with single-dose t½) at higher doses (1000 and 1500 mg). There was no age effect or diurnal variation in the GSK1322322 pharmacokinetic profile. GSK1322322 was generally well tolerated-all adverse events were mild to moderate in intensity. CONCLUSIONS Repeat oral GSK1322322 (500-1500 mg) for 10 days was well tolerated. These data warrant further clinical investigation of GSK1322322.

Effects of Formulation and Dosing Strategy on Amprenavir Concentrations in the Seminal Plasma of Human Immunodeficiency Virus Type 1-Infected Men

We compared seminal plasma pharmacokinetic data for the investigational amprenavir prodrug GW433908 with those for amprenavir and an amprenavir-ritonavir combination regimen. All 3 regimens resulted in detectable blood plasma and seminal plasma concentrations of amprenavir. The majority of these concentrations were greater than the plasma protein-corrected 50% inhibitory concentration for wild-type human immunodeficiency virus type 1.

A 42-Week Open-Label Study to Assess the Pharmacokinetics, Antiretroviral Activity, and Safety of Amprenavir or Amprenavir plus Ritonavir in Combination with Abacavir and Lamivudine for Treatment of HIV-Infected Patients

The pharmacokinetics, antiviral activity, and safety of an amprenavir-ritonavir (APV-RTV) 600/100 mg b.i.d. regimen and an APV-RTV 1200/200 mg q.d. regimen were studied in a human immunodeficiency virus (HIV)-infected population. The geometric least-square mean ratio (90% confidence interval) of steady-state trough concentrations, compared with that of the amprenavir 1200 mg b.i.d. regimen, was 6.08 (4.94-7.49) for the twice-daily APV-RTV regimen, and it was 4.19 (2.90-6.08) for the daily APV-RTV regimen. The regimens were well tolerated, which supports APV-RTV as an option for twice-daily or daily therapy for HIV.

Effect of H2 Blockade and Food on Single-Dose Pharmacokinetics of GSK1322322, a Peptide Deformylase Inhibitor Antibacterial

ABSTRACT GSK1322322 is first in a new class of antibiotics, peptide deformylase inhibitors, and is active against multidrug-resistant respiratory and skin pathogens. Part 1 of this phase 1, randomized, single-dose (1,000 mg) study in 20 healthy volunteers compared the relative bioavailability of three different tablet formulations of GSK1322322 (fast release, intermediate release, and slow release) to that of the previously studied powder-in-bottle formulation to assess the optimal formulation for progression into clinical trials. Part 2 assessed the effect of a high-fat meal and drug interaction with an H2 blocker and an H2 blocker plus vitamin C on the pharmacokinetic profile of GSK1322322. Of the three tablet formulations, fast-release GSK1322322 provided pharmacokinetic profiles similar to those of the powder-in-bottle reference formulation (∼93% relative bioavailability) and was selected for progression in part 2. When GSK1322322 was administered with a high-fat meal, the maximum observed plasma concentration (Cmax) was reduced by 20%, and the time to maximum plasma concentration (Tmax) was delayed by 1.9 h. The exposure (area under the concentration-time curve [AUC]) increased by ∼20% compared to that in volunteers in the fasted state. Coadministration of GSK1322322 with an H2 blocker resulted in a slight delay in absorption (Tmax ∼0.75 h later) and 58 and 38% decreases in the Cmax and AUC0–∞ values, respectively, compared to GSK1322322 alone. This effect was reversed with vitamin C intake (i.e., no delay in Tmax and the Cmax and AUC0–∞ values decreased by only 21 and 12%, respectively). GSK1322322 was generally well tolerated, and most adverse events were mild in intensity during both parts of the study.

Microbiome Changes in Healthy Volunteers Treated with GSK1322322, a Novel Antibiotic Targeting Bacterial Peptide Deformylase

ABSTRACT GSK1322322 is a novel antibacterial agent under development, and it has known antibacterial activities against multidrug-resistant respiratory and skin pathogens through its inhibition of the bacterial peptide deformylase. Here, we used next-generation sequencing (NGS) of the bacterial 16S rRNA genes from stool samples collected from 61 healthy volunteers at the predosing and end-of-study time points to determine the effects of GSK1322322 on the gastrointestinal (GI) microbiota in a phase I, randomized, double-blind, and placebo-controlled study. GSK1322322 was administered either intravenously (i.v.) only or in an oral-i.v. combination in single- and repeat-dose-escalation infusions. Analysis of the 16S rRNA sequence data found no significant changes in the relative abundances of GI operational taxonomic units (OTUs) between the prestudy and end-of-study samples for either the placebo- or i.v.-only-treated subjects. However, oral-i.v. treatment resulted in significant decreases in some bacterial taxa, the Firmicutes and Bacteroidales, and increases in others, the Betaproteobacteria, Gammaproteobacteria, and Bifidobacteriaceae. Microbiome diversity plots clearly differentiated the end-of-study oral-i.v.-dosed samples from all others collected. The changes in genome function as inferred from species composition suggest an increase in bacterial transporter and xenobiotic metabolism pathways in these samples. A phylogenetic analysis of the peptide deformylase protein sequences collected from the published genomes of clinical isolates previously tested for GSK1322322 in vitro susceptibility and GI bacterial reference genomes suggests that antibiotic target homology is one of several factors that influences the response of GI microbiota to this antibiotic. Our study shows that dosing regimen and target class are important factors when considering the impact of antibiotic usage on GI microbiota. (This clinical trial was registered at the GlaxoSmithKline Clinical Study Register under study identifier PDF 113376.)